The Science Behind Coronavirus Testing, and Where the U.S. Went Wrong

To detect a virus, we just have to look for its instruction manual.

How does the coronavirus test work?

To answer these questions, let’s first consider the culprit the test aims to detect: the virus itself. Viruses, at their core, are surprisingly simple entities: capsules with machinery to penetrate a cell, containing genetic information with instructions to make more viruses. Once a virus enters a cell, the instructions are read and more viral parts are made and assembled. Newly made viruses have mechanisms to escape their host cells and, in the case of coronavirus, travel further down the respiratory tract, eventually reaching the lung cells. When infected, lung cells can no longer perform their normal jobs, leading to the respiratory symptoms of Covid-19 (the disease caused by the novel coronavirus).

The novel coronavirus enters and multiplies inside our cells

The coronavirus test is relatively simple, and operationally the same in every country.

(To be totally accurate, coronavirus is actually an RNA virus. RNA is similar to DNA, but this method looks a little different in practice and is referred to as RT-PCR. The outcome is the same: Many, many copies of the DNA are made from the viral RNA instructions.)

If the test is so simple, why is the U.S. having trouble getting it to work?

The U.S. initially mandated the use of CDC-developed test kits for all coronavirus testing, but labs reportedly had trouble getting them to work. The CDC was criticized for not using test kits developed in Germany, which were successfully detecting coronavirus around the world and were backed by WHO. U.S. labs responded by developing their own tests, and in some cases reporting quicker turnaround of results. This prompts the question: What are the differences between these tests and why do some work better than others?

Most molecular biology labs can develop such a test in a week or two, but those who have done so have come against another major hurdle: FDA regulations.

Choosing primers for any PCR experiment turns out to be tricky and sometimes unpredictable. Primers are just short pieces of DNA themselves, and some DNA has a tendency to fold in on itself, creating a “hairpin” structure which inhibits PCR. (This is a bit like the matching letters in a palindrome finding one another). These “palindrome” primers can produce a false negative — an infected patient whose sample appears to lack the virus. Alternatively, the primers can work just fine to make copies of coronavirus RNA, but might also be capable of copying some part of human DNA. Because patient samples (most often nasal swabs) contain both viral particles and human cells, these primers can produce a false positive — an uninfected individual testing positive for the virus. Other potential sources of RT-PCR failure are temperature issues, low primer or sample concentration, and contamination, among others.

How a coronavirus test can fail. A “palindrome” primer can cause a false negative. Primers which can recognize human DNA can lead to a false positive.

Federal regulations complicate in-house testing

Before we get into the weeds here, it is important to remind ourselves why FDA regulations exist: to protect the consumer — us — from being given incorrect medical information. Typically, there is regulatory oversight both of the laboratories where clinical tests are performed and of the tests themselves (though as this article points out, prior to this outbreak, FDA oversight of clinical tests under the current administration has been alarmingly slim).

Massive supply shortages require creative solutions

Labs that manage to get proper certification to run clinical testing face another hurdle: a massive shortage of supplies. Patient samples are most commonly collected as nasal swabs, and before RT-PCR, viral RNA must be separated from mucous, human cells, and other debris. Commercially available RNA extraction kits are by far the quickest and safest way to process many samples at once, but unsurprisingly, demand has quickly outpaced supply, forcing testing labs to seek donations locally via social media.

Will drive-thru & at-home testing help?

First, let’s clear up some confusion here. When it comes to coronavirus testing, “drive-thru” and “at-home” do not describe the test itself, which requires training and specialized equipment. These terms refer instead to how and where nasal swabs are collected. Though these strategies may not substantially increase the speed of testing, there may be immense public health benefits to performing sample collection via mail or a drive-thru point. Why? Because those who fear they are ill need not travel to a clinic, risking infecting others while there or in transit. Plans to implement at-home sample collection are already in progress, and drive-thru testing is already available for UW Medicine patients and staff. But regulatory hurdles exist in this domain as well. To process at-home tests, labs must provide substantial evidence that these samples are reliable relative to those collected by trained individuals, further hampering labs’ ability to quickly roll out these operations.

Where do we go from here?

The challenges outlined here all converge around one conclusion: The U.S. was completely unprepared for a public health emergency of this scale. South Korea revamped its emergency preparedness plans after the MERS outbreak of 2015, recognizing that early detection and isolation were effective to mitigate an outbreak, and putting resources and procedures into place which could be mobilized quickly.

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